Transdermal drug delivery systems for levonorgestrel and ethinyl estradiol

ABSTRACT

Described are transdermal drug delivery systems for the transdermal administration of levonorgestrel and ethinyl estradiol, comprising an acrylic polymer matrix. Methods of making and using such systems also are described.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit under 35 USC §119(e) to U.S.provisional application 61/747,013, filed Dec. 28, 2012, the entirecontents of which are incorporated herein by reference in theirentirety.

FIELD OF THE INVENTION

Described herein are compositions and methods for the transdermaldelivery of levonorgestrel and ethinyl estradiol. The compositions andmethods are useful, for example, as contraceptives.

BACKGROUND

Transdermal delivery systems (adhesive patches) as dosage forms havebeen the subject of a vast number of patent applications over the last25 years, yielding many patents but few commercial products incomparison. To those working in the field, the relatively small numberof commercial products is not surprising. Although regulatory, economic,and market hurdles play a role in limiting the number of products on themarket, the task of developing a transdermal delivery system thatachieves desired physical and pharmacokinetic parameters to satisfyphysician and patient demand is more daunting. Parameters to beconsidered during commercial product development may include drugsolubility, drug stability (e.g., as may arise from interaction withother component materials and/or the environment), delivery of atherapeutic amount of drug at a desired delivery rate over the intendedduration of use, adequate adhesion at the anatomical site ofapplication, integrity (e.g., minimal curling, wrinkling, delaminatingand slippage) with minimal discomfort, irritation and sensitization bothduring use and during and after removal, and minimal residual adhesive(or other components) after removal. Size also may be important from amanufacturing and patient viewpoint, and appearance may be importantfrom a patient viewpoint. These factors become even more complicatedwhen more than one drug is being formulated.

This invention relates generally to transdermal drug delivery systems,and more particularly, to transdermal drug delivery systems for thedelivery of levonorgestrel and ethinyl estradiol.

U.S. Pat. No. 7,045,145 is directed to a transdermal delivery systemcomprising a backing layer, and an adhesive polymer matrix affixed tothe backing layer, wherein the adhesive polymer matrix is formulated bycombining, on a weight percentage basis: (a) from about 0% to about 10%of a humectant/plasticizer; (b) from about 20% to about 70% of anadhesive copolymer; (c) from about 10% to about 60% percent of acombination of skin permeation enhancing agents which is a mixturecomprising dimethyl sulfoxide, a fatty (C8-C20) alcohol ester of lacticacid, a lower (C1-C4) alkyl ester of lactic acid and capric acid presentin ratio ranging from about 2:1:1:0.8 to about 6:1:1:0.8, respectively;(d) a progestin hormone; and (e) an estrogen hormone.

U.S. Pat. No. 7,384,650 is directed to a transdermal hormone deliverysystem comprising a backing layer and an adhesive polymer matrix affixedto the backing layer, wherein the adhesive polymer matrix comprises: (a)an adhesive polymer; (b) a humectant; (c) a combination of skinpermeation enhancing agents consisting essentially of, on a finalpercentage by weight of the adhesive polymer matrix after fabrication ofthe system, from about 4% to about 12% dimethyl sulfoxide; from about4.2% to about 12.6% a fatty (C8-C20) alcohol ester of lactic acid; fromabout 0.7% to about 2.3% lower (C1-C4) alkyl ester of lactic acid; andfrom about 3% to about 9% capric acid; (d) a progestin; and (e) anestrogen.

U.S. Pat. No. 8,221,785 is directed to a contraceptive delivery systemcomprising a backing layer and an adhesive polymer matrix affixed to thebacking layer, wherein the adhesive polymer matrix comprises: (a) anadhesive polymer comprising a polyacrylate copolymer; (b) a humectantcomprising polyvinylpyrrolidone; (c) a combination of skin permeationenhancing agents consisting essentially of, on a final percentage byweight of the adhesive polymer matrix after fabrication of the system,from about 4% to about 12% dimethyl sulfoxide; from about 4.2% to about12.6% a fatty (C8-C20) alcohol ester of lactic acid; from about 0.7% toabout 2.3% lower (C1-C4) alkyl ester of lactic acid; and from about 3%to about 9% capric acid; (d) levonorgestrel; and (e) ethinyl estradiolor 17 beta-estradiol.

U.S. Pat. No. 5,770,219 is directed to a drug-containing matrix for usein a transdermal drug delivery device for administering at least oneestrogen to an area of skin or mucosa comprising the estrogen dispersedin a body of a pressure sensitive adhesive, said pressure-sensitiveadhesive comprising an acetate acrylate copolymer andpolyvinylpyrrolidone, said matrix being essentially free of a skinpermeation enhancer. In some embodiments, the matrix further compriseslevonorgestrel.

Nevertheless, the transdermal delivery of levonorgestrel and ethinylestradiol continues to present challenges, and currently there is nocommercial transdermal combination product on the market. Some of thechallenges presented by this particular drug combination include thehigh delivery rate of levonorgestrel and its impact on patch size; theundesired crystallization of levonorgestrel in the polymer matrix; andthe difficulty of formulating a composition that can achieve sustaineddrug delivery (e.g., at therapeutic levels) over a period of time of 7days.

Thus, there remains a need for transdermal drug delivery systemsdesigned for the delivery of specific drugs and drug combinations, suchas levonorgestrel and ethinyl estradiol.

SUMMARY

In accordance with some embodiments, there are provided transdermal drugdelivery systems for the transdermal delivery of levonorgestrel andethinyl estradiol in the form of a flexible finite system for topicalapplication, comprising a polymer matrix comprising levonorgestrel,ethinyl estradiol, and an acrylic polymer, wherein the acrylic polymermay comprise a hydroxy functional acrylic polymer. In some embodiments,the polymer matrix is substantially free of or free ofpolyvinylpyrrolidone (PVP) and polyvinylpyrrolidone/vinylacetate(PVP/VA).

In some embodiments, the transdermal drug delivery system furthercomprises a penetration enhancer. In specific embodiments, the polymermatrix comprises 0.1 to 3% levonorgestrel; 0.1 to 5% ethinyl estradiol;5 to 20% penetration enhancer, and the balance acrylic polymer. In anyembodiments, the penetration enhancer may be glyceryl monooleate,dipropylene glycol, or mixtures thereof.

In any embodiments, the transdermal drug delivery system may comprise anamount of levonorgestrel sufficient to achieve sustained delivery oflevonorgestrel over a period of time of at least 3 days, at least 4days, or at least 7 days.

In any embodiments, the transdermal drug delivery system may comprise anamount of ethinyl estradiol sufficient to achieve sustained delivery ofethinyl estradiol over a period of time of at least 3 days, at least 4days, or at least 7 days.

In any embodiments, the transdermal drug delivery system may furthercomprise a backing layer and/or a release liner.

Also provided are methods of transdermally delivering levonorgestrel andethinyl estradiol comprising applying a transdermal drug delivery systemas described herein to the skin or mucosa of a subject in need thereof.In some embodiments, the subject is a human female subject. In someembodiments, the method is for contraception. In some embodiments, thetransdermal drug delivery system is applied for a duration of up to 7days.

Also provided are methods of preparing a transdermal drug deliverysystem comprising levonorgestrel and ethinyl estradiol as describedherein, comprising preparing a polymer matrix as described herein,comprising levonorgestrel, ethinyl estradiol, and an acrylic polymer.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates the levonorgestrel flux (μg/cm²/hr) over time (0-160hours) from a transdermal delivery system according to the invention(−), as compared to Climara® Pro (▪).

FIG. 2 illustrates the ethinyl estradiol flux (μg/cm²/hr) over time(0-160 hours) from a transdermal delivery system according to theinvention (♦), as compared to OrthoEvra® (▪).

FIG. 3 illustrates the effect of ethinyl estradiol concentration onethinyl estradiol flux (μg/cm²/hr) over time (0-160 hours) from atransdermal delivery system according to the invention (♦, ▴, -x-), ascompared to OrthoEvra® (▪).

DETAILED DESCRIPTION

In accordance with some embodiments, the present invention providestransdermal drug delivery systems for the transdermal delivery oflevonorgestrel and ethinyl estradiol. In specific embodiments, thesystems exhibit desired pharmacokinetic properties, such as by beingcapable of formulation for use over a 7 day period, and/or exhibitdesired stability characteristics, such as reduced or minimizedcrystallization of levonorgestrel.

The present inventors surprisingly discovered that levonorgestrel andethinyl estradiol could be formulated together in a polymer matrixwithout the need for humectant such as polyvinylpyrollidone (PVP) orpolyvinylpyrollidone/vinylacetate (PVP/VA). The present inventors alsosurprisingly discovered that acrylic polymers comprising hydroxyfunctional groups (such as hydroxyl functional group containing vinylacetates) are particularly suitable for formulating levonorgestrel forsustained delivery over an extended period of time (such as 7 days). Thepresent inventors also surprisingly discovered that each of dipropyleneglycol (DPG) and glyceryl monooleate (GMO) alone or in combination areeffective enhancers for levonorgestrel.

In accordance with some aspects, there are provided transdermal drugdelivery systems and methods for the transdermal delivery oflevonorgestrel and ethinyl estradiol. In specific embodiments, thesystems exhibit sustained delivery of levonorgestrel and ethinylestradiol over an extended period of time, such as for at least 3 days,4 days, 7 days, or longer.

Definitions

Technical and scientific terms used herein have the meanings commonlyunderstood by one of ordinary skill in the art to which the presentinvention pertains, unless otherwise defined. Reference is made hereinto various methodologies known to those of ordinary skill in the art.Publications and other materials setting forth such known methodologiesto which reference is made are incorporated herein by reference in theirentireties as though set forth in full. Any suitable materials and/ormethods known to those of ordinary skill in the art can be utilized incarrying out the present invention. However, specific materials andmethods are described. Materials, reagents and the like to whichreference is made in the following description and examples areobtainable from commercial sources, unless otherwise noted.

As used herein, the singular forms “a,” “an,” and “the” designate boththe singular and the plural, unless expressly stated to designate thesingular only.

The term “about” and the use of ranges in general, whether or notqualified by the term about, means that the number comprehended is notlimited to the exact number set forth herein, and is intended to referto ranges substantially within the quoted range while not departing fromthe scope of the invention. As used herein, “about” will be understoodby persons of ordinary skill in the art and will vary to some extent onthe context in which it is used. If there are uses of the term which arenot clear to persons of ordinary skill in the art given the context inwhich it is used, “about” will mean up to plus or minus 10% of theparticular term.

The phrase “substantially free” as used herein generally means that thedescribed composition (e.g., transdermal drug delivery system, polymermatrix, etc.) comprises less than about 5%, less than about 3%, or lessthan about 1% by weight, based on the total weight of the composition atissue, of the excluded component. The phrase “free of” as used hereinmeans that the described composition (e.g., polymer matrix, etc.) isformulated without adding the excluded component(s) as an intendedcomponent, although trace amounts may be present in other components oras a by-product or contaminant, such that the composition comprises atmost only trace amounts of the excluded component(s).

As used herein “subject” denotes any animal in need of drug therapy,including humans. For example, a subject may be suffering from or atrisk of developing a condition that can be treated or prevented withlevonorgestrel and ethinyl estradiol, or may be taking levonorgestreland ethinyl estradiol for health maintenance purposes. In specificembodiments, the subject is a female subject taking levonorgestrel andethinyl estradiol for contraceptive purposes.

As used herein, the phrases “therapeutically effective amount” and“therapeutic level” mean that drug dosage or plasma concentration in asubject, respectively, that provides the specific pharmacologicalresponse for which the drug is administered in a subject in need of suchtreatment. It is emphasized that a therapeutically effective amount ortherapeutic level of a drug will not always be effective in treating theconditions/diseases described herein, even though such dosage is deemedto be a therapeutically effective amount by those of skill in the art.For convenience only, exemplary dosages, drug delivery amounts,therapeutically effective amounts and therapeutic levels are providedbelow with reference to adult human subjects. Those skilled in the artcan adjust such amounts in accordance with standard practices as neededto treat a specific subject and/or condition/disease.

As used herein, “active surface area” means the surface area of thedrug-containing layer of the transdermal drug delivery system.

As used herein, “coat weight” refers to the weight of thedrug-containing layer per unit area of the active surface area of thetransdermal drug delivery system.

As used herein, “flux” (also called “permeation rate”) is defined as theabsorption of a drug through skin or mucosal tissue, and is described byFick's first law of diffusion:J=−D(dCm/dx)

where J is the flux in g/cm2/sec, D is the diffusion coefficient of thedrug through the skin or mucosa in cm2/sec and dCm/dx is theconcentration gradient of the drug across the skin or mucosa.

As used herein, the term “transdermal” refers to delivery,administration or application of a drug by means of direct contact withskin or mucosa. Such delivery, administration or application is alsoknown as dermal, percutaneous, transmucosal and buccal. As used herein,“dermal” includes skin and mucosa, which includes oral, buccal, nasal,rectal and vaginal mucosa.

As used herein, “transdermal drug delivery system” refers to a system(e.g., a device) comprising a composition that releases drug uponapplication to the skin (or any other surface noted above). Atransdermal drug delivery system may comprise a drug-containing layer,and, optionally, a backing layer and/or a release liner layer. In someembodiments, the transdermal drug delivery system is a substantiallynon-aqueous, solid form, capable of conforming to the surface with whichit comes into contact, and capable of maintaining such contact so as tofacilitate topical application without adverse physiological response,and without being appreciably decomposed by aqueous contact duringtopical application to a subject. Many such systems are known in the artand commercially available, such as transdermal drug delivery patches.As described below, in one embodiment, the transdermal drug deliverysystem comprises a drug-containing polymer matrix that comprises apressure-sensitive adhesive or bioadhesive, and is adopted for directapplication to a user's (e.g., a subject's) skin. In other embodiments,the polymer matrix is non-adhesive and may be provided with separateadhesion means (such as a separate adhesive layer) for application andadherence to the user's skin.

As used herein, “polymer matrix” refers to a polymer composition whichcontains one or more drugs. In some embodiments, the matrix comprises apressure-sensitive adhesive polymer or a bioadhesive polymer. In otherembodiments, the matrix does not comprise a pressure-sensitive adhesiveor bioadhesive. As used herein, a polymer is an “adhesive” if it has theproperties of an adhesive per se, or if it functions as an adhesive bythe addition of tackifiers, plasticizers, crosslinking agents or otheradditives. Thus, in some embodiments, the polymer matrix comprises apressure-sensitive adhesive polymer or a bioadhesive polymer, with drugdissolved or dispersed therein. The polymer matrix also may comprisetackifiers, plasticizers, crosslinking agents, enhancers, co-solvents,fillers, antioxidants, solubilizers, crystallization inhibitors, orother additives described herein. U.S. Pat. No. 6,024,976 describespolymer blends that are useful in accordance with the transdermalsystems described herein. The entire contents of U.S. Pat. No. 6,024,976is incorporated herein by reference.

As used herein, the term “pressure-sensitive adhesive” refers to aviscoelastic material which adheres instantaneously to most substrateswith the application of very slight pressure and remains permanentlytacky. A polymer is a pressure-sensitive adhesive within the meaning ofthe term as used herein if it has the properties of a pressure-sensitiveadhesive per se or functions as a pressure-sensitive adhesive byadmixture with tackifiers, plasticizers or other additives.

The term pressure-sensitive adhesive also includes mixtures of differentpolymers and mixtures of polymers, such as polyisobutylenes (PIB), ofdifferent molecular weights, wherein each resultant mixture is apressure-sensitive adhesive. In the last case, the polymers of lowermolecular weight in the mixture are not considered to be “tackifiers,”said term being reserved for additives which differ other than inmolecular weight from the polymers to which they are added.

In some embodiments, the polymer matrix is a pressure-sensitive adhesiveat room temperature and has other desirable characteristics foradhesives used in the transdermal drug delivery art. Suchcharacteristics include good adherence to skin, ability to be peeled orotherwise removed without substantial trauma to the skin, retention oftack with aging, etc. In some embodiments, the polymer matrix has aglass transition temperature (Tg), measured using a differentialscanning calorimeter, of between about −70° C. and 0° C.

As used herein, the term “rubber-based pressure-sensitive adhesive”refers to a viscoelastic material which has the properties of apressure-sensitive adhesive and which contains at least one natural orsynthetic elastomeric polymer.

In some embodiments, the transdermal drug delivery system includes oneor more additional layers, such as one or more additional polymer matrixlayers, or one or more adhesive layers that adhere the transdermal drugdelivery system to the user's skin. In other embodiments, thetransdermal drug delivery system is monolithic, meaning that itcomprises a single polymer matrix layer comprising a pressure-sensitiveadhesive or bioadhesive with drug dissolved or dispersed therein, and norate-controlling membrane.

The transdermal drug delivery system also may include a drug impermeablebacking layer or film. In some embodiments, the backing layer isadjacent one face of the polymer matrix layer. When present, the backinglayer protects the polymer matrix layer (and any other layers present)from the environment and prevents loss of the drug and/or release ofother components to the environment during use. Materials suitable foruse as backing layers are well-known known in the art and can comprisefilms of polyester, polyethylene, vinyl acetate resins, ethylene/vinylacetate copolymers, polyvinyl chloride, polyurethane, and the like,metal foils, non-woven fabric, cloth and commercially availablelaminates. A typical backing material has a thickness in the range of 2to 1000 micrometers. For example, 3M's Scotch Pak™ 1012 or 9732 backingmaterial (a polyester film with an ethylene vinyl acetate copolymer heatseal layer) is useful in the transdermal drug delivery systems describedherein.

The transdermal drug delivery system also may include a release liner,typically located adjacent the opposite face of the system as comparedto the backing layer. When present, the release liner is removed fromthe system prior to use to expose the polymer matrix layer and/or anadhesive layer prior to topical application. Materials suitable for useas release liners are well-known known in the art and include thecommercially available products of Dow Corning Corporation designatedBio-Release® liner and Syl-off® 7610 (both silicone-based) and 3M's1020, 1022, 9744, 9748 and 9749 Scotchpak™ (fluoropolymer coatedpolyester films).

The transdermal drug delivery system may be packaged or provided in apackage, such as a pouchstock material used in the prior art fortransdermal drug delivery systems in general. For example, DuPont'sSurlyn® can be used in a pouchstock material.

As used herein, a “monolithic” transdermal drug delivery system mayinclude a backing layer and/or release liner, and may be provided in apackage.

Polymer Matrix

In accordance with some embodiments, the compositions described hereincomprise a polymer matrix that comprises, consists essentially of, orconsists of levonorgestrel, ethinyl estradiol, at least one acrylicpolymer, and, optionally, at least one penetration enhancer. In thiscontext, the phrase “consists essentially of” means that the polymermatrix is substantially free of other polymer components (e.g.,substantially free of polymers other than one or more acrylic polymers)although it may include other excipients known to be useful intransdermal compositions (such as tackifiers, plasticizers, crosslinkingagents or other excipients known in the art) as long as those otherexcipients do not degrade the physical and/or pharmacokinetic propertiesof the compositions to pharmaceutically unacceptable levels.

In some embodiments, the compositions described herein are free of orare substantially free of a humectant, such as polyvinylpyrrolidone(PVP) and polyvinylpyrrolidone/vinylacetate (PVP/VA), as used in U.S.Pat. No. 7,045,145. As noted above, the present inventors surprisinglydiscovered that stable compositions could be prepared without PVP orPVP/VA. While PVP typically is believed to suppress crystal formation intransdermal drug delivery systems, the inventors surprisingly discoveredthat levonorgestrel formulations that are substantially free of or freeof PVP exhibit less crystallization than levonorgestrel formulationsthat comprise PVP.

In some embodiments, the polymer matrix comprises (on a weight % basis)about 0.1-3% levonorgestrel, about 0.1-5% ethinyl estradiol, about 5-20%penetration enhancer(s), and the balance acrylic polymer(s).

Levonorgestrel

Levonorgestrel is a synthetic progestogen. It is an enantiomer of thechiral compound13-ethyl-17-ethynyl-17-hydroxy-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydrocyclopenta[a]phenanthren-3-one.

Ethinyl Estradiol

Ethinyl estradiol is an estrogen with the chemical name19-nor-17α-pregna-1,3,5(10)-trien-20-yne-3,17-diol.

The amount of levonorgestrel and ethinyl estradiol to be incorporated inthe polymer matrix varies depending on the desired therapeutic effect,and the time span for which the system is to provide therapy. For mostdrugs, the passage of the drugs through the skin will be therate-limiting step in delivery. A minimum amount of drug in the systemis selected based on the amount of drug which passes through the skin inthe time span for which the system is to provide therapy. In someembodiments, a system for the transdermal delivery of levonorgestrel andethinyl estradiolis used over a period of about 1 day, about 3 days,about 7 days, or longer. Thus, in one embodiment, the systems comprisean amount of drug (e.g., levonorgestrel and ethinyl estradiol)sufficient to deliver therapeutically effective amounts of drug over aperiod of from 1 day to 3 days, 7 days, or longer, including for 1 day,for 2 days, for 3 days, for 4 days, for 5 days, for 6 days, for 7 days,or for longer.

The inventors surprisingly discovered that the amount of ethinylestradiol can be selected and controlled to select and control thetransdermal delivery of ethinyl estradiol without substantiallyimpacting the transdermal delivery of levonorgestrel. That is, the fluxof ethinyl estradiol can be increased by increasing the relative amountof ethinyl estradiol without substantially impacting the transdermaldelivery of levonorgestrel.

In some embodiments, the polymer matrix comprises from about 0.1% toabout 50%, including from about 1% to about 20%, such as from about 1%to about 10% by weight, of active agent. In some embodiments, thepolymer matrix comprises from about 0.1% to about 25%, including fromabout 1% to about 10%, such as from about 1% to about 5% by weight, oflevonorgestrel. In some embodiments, the polymer matrix comprises fromabout 0.1% to about 25%, including from about 1% to about 10%, such asfrom about 1% to about 5% by weight, of ethinyl estradiol.

In some embodiments, the polymer matrix comprises from about 0.1 to 3%or 0.1 to 5% by weight levonorgestrel. In some embodiments, the polymermatrix comprises from about 0.1 to 3% or 0.1 to 5% by weight ethinylestradiol.

Acrylic Polymers

The term “acrylic polymer” is used here as in the art interchangeablywith “polyacrylate,” “polyacrylic polymer,” and “acrylic adhesive.” Theacrylic-based polymers can be any of the homopolymers, copolymers,terpolymers, and the like of various acrylic acids or esters. In someembodiments, the acrylic-based polymers are adhesive polymers. In otherembodiments, the acrylic-based polymers function as an adhesive by theaddition of tackifiers, plasticizers, crosslinking agents or otheradditives.

The acrylic polymer can include copolymers, terpolymers andmultipolymers. For example, the acrylic polymer can be any of thehomopolymers, copolymers, terpolymers, and the like of various acrylicacids. In some embodiments, the amount and type of acrylic polymer isdependent on the amounts of levonorgestrel and ethinyl estradiol used.

Acrylic polymers useful in practicing the invention include polymers ofone or more monomers of acrylic acids and other copolymerizablemonomers. The acrylic polymers also include copolymers of alkylacrylates and/or methacrylates and/or copolymerizable secondary monomersor monomers with functional groups. Combinations of acrylic-basedpolymers based on their functional groups is also contemplated.Acrylic-based polymers having functional groups include copolymers andterpolymers which contain, in addition to nonfunctional monomer units,further monomer units having free functional groups. The monomers can bemonofunctional or polyfunctional. By varying the amount of each type ofmonomer added, the cohesive properties of the resulting acrylic polymercan be changed as is known in the art. In some embodiments, the acrylicpolymer is composed of at least 50% by weight of an acrylate or alkylacrylate monomer, from 0 to 20% of a functional monomer copolymerizablewith the acrylate, and from 0 to 40% of other monomers.

Acrylate monomers which can be used include acrylic acid and methacrylicacid and alkyl acrylic or methacrylic esters such as methyl acrylate,ethyl acrylate, propyl acrylate, amyl acrylate, butyl acrylate, butylmethacrylate, hexyl acrylate, methyl methacrylate, hexyl methacrylate,heptyl acrylate, octyl acrylate, nonyl acrylate, 2-ethylbutyl acrylate,2-ethylbutyl methacrylate, isooctyl acrylate, isooctyl methacrylate,2-ethylhexyl acrylate, 2-ethylhexyl methacrylate, decyl acrylate, decylmethacrylate, dodecyl acrylate, dodecyl methacrylate, tridecyl acrylate,tridecyl methacrylate, glycidyl acrylate, and corresponding methacrylicesters.

Non-functional acrylic-based polymers can include any acrylic basedpolymer having no or substantially no free functional groups.

Functional monomers, copolymerizable with the above alkyl acrylates ormethacrylates, which can be used include acrylic acid, methacrylic acid,maleic acid, maleic anhydride, hydroxyethyl acrylate, hydroxypropylacrylate, acrylamide, dimethylacrylamide, acrylonitrile,dimethylaminoethyl acrylate, dimethylaminoethyl methacrylate,tert-butylaminoethyl acrylate, tert-butylaminoethyl methacrylate,methoxyethyl acrylate and methoxyethyl methacrylate.

As used herein, “functional monomers or groups,” are monomer unitstypically in acrylic-based polymers which have reactive chemical groupswhich modify the acrylic-based polymers directly or which provide sitesfor further reactions. Examples of functional groups include carboxyl,epoxy, hydroxyl, sulfoxyl, and amino groups. Acrylic-based polymershaving functional groups contain, in addition to the nonfunctionalmonomer units described above, further monomer units having freefunctional groups. The monomers can be monofunctional or polyfunctional.These functional groups include carboxyl groups, hydroxy groups, aminogroups, amido groups, epoxy groups, etc. Typical carboxyl functionalmonomers include acrylic acid, methacrylic acid, itaconic acid, maleicacid, and crotonic acid. Typical hydroxy functional monomers include2-hydroxyethyl methacrylate, 2-hydroxyethyl acrylate, hydroxymethylacrylate, hydroxymethyl methacrylate, hydroxyethyl acrylate,hydroxyethyl methacrylate, hydroxypropyl acrylate, hydroxypropylmethacrylate, hydroxybutyl acrylate, hydroxybutyl methacrylate,hydroxyamyl acrylate, hydroxyamyl methacrylate, hydroxyhexyl acrylate,hydroxyhexyl methacrylate. As noted above, in some embodiments, theacrylic polymer does not include such functional groups.

In some embodiments, the acrylic polymer includes hydroxy functionalmonomers. Such polymers generally exhibit good solubility forlevonorgestrel, which allows sufficient loading of levonorgestrel forpreparation of a system that achieves transdermal delivery of atherapeutically effective amount of active agent over an extended periodof time, such as a period of at least 3 days, at least 4 days, or atleast 7 days, or longer.

Further details and examples of acrylic adhesives which are suitable inthe practice of the invention are described in Satas, “AcrylicAdhesives,” Handbook of Pressure-Sensitive Adhesive Technology, 2nd ed.,pp. 396-456 (D. Satas, ed.), Van Nostrand Reinhold, New York (1989);“Acrylic and Methacrylic Ester Polymers,” Polymer Science andEngineering, Vol. 1, 2nd ed., pp 234-268, John Wiley & Sons, (1984);U.S. Pat. No. 4,390,520; and U.S. Pat. No. 4,994,267, all of which areexpressly incorporated by reference in their entireties.

Suitable acrylic polymers also include pressure-sensitive adhesiveswhich are commercially available, such as the acrylic-based adhesivessold under the trademarks DURO-TAK® by National Starch and ChemicalCorporation, Bridgewater, N.J. (such as DURO-TAK® 87-2516, 87-2287,-4098, -2852, -2196, -2296, -2194, -2516, -2070, -2353, -2154, -2510,-9085, -9088 and 73-9301). Other suitable acrylic adhesives includethose sold under the trademark EUDRAGIT® by Roehm Pharma GmbH,Darmstadt, Germany, those sold by Cytec Surface Specialties, St. Louis,Mo., under the trademarks GELVA® Multipolymer Solution (such as GELVA®2480, 788, 737, 263, 1430, 1753, 1151, 2450, 2495, 3067, 3071, 3087 and3235). For example, hydroxy functional adhesives with a reactivefunctional OH group in the polymeric chain, can be used. Non-limitingcommercial examples of this type of adhesives include both GELVA® 737,788, and 1151 and DURO-TAK® 87-2287, -4287, -2510 and -2516.

In some embodiments, the acrylic polymer constitutes up to 100% byweight of the polymer content of the polymer matrix, including 100%

Other Components

In one embodiment, the polymer matrix comprises a penetration enhancer.A “penetration enhancer” is an agent known to accelerate the delivery ofthe drug through the skin. These agents also have been referred to asaccelerants, adjuvants, and sorption promoters, and are collectivelyreferred to herein as “enhancers.” This class of agents includes thosewith diverse mechanisms of action, including those which have thefunction of improving percutaneous absorption, for example, by changingthe ability of the stratum corneum to retain moisture, softening theskin, improving the skin's permeability, acting as penetrationassistants or hair-follicle openers or changing the state of the skinincluding the boundary layer.

Illustrative penetration enhancers include but are not limited topolyhydric alcohols such as dipropylene glycol, propylene glycol, andpolyethylene glycol; oils such as olive oil, squalene, and lanolin;fatty ethers such as cetyl ether and oleyl ether; fatty acid esters suchas isopropyl myristate; urea and urea derivatives such as allantoinwhich affect the ability of keratin to retain moisture; polar solventssuch as dimethyldecylphosphoxide, methyloctylsulfoxide,dimethyllaurylamide, dodecylpyrrolidone, isosorbitol, dimethylacetonide,dimethylsulfoxide, decylmethylsulfoxide, and dimethylformamide whichaffect keratin permeability; salicylic acid which softens the keratin;amino acids which are penetration assistants; benzyl nicotinate which isa hair follicle opener; and higher molecular weight aliphaticsurfactants such as lauryl sulfate salts which change the surface stateof the skin and drugs administered. Other agents include oleic andlinoleic acids, ascorbic acid, panthenol, butylated hydroxytoluene,tocopherol, tocopheryl acetate, tocopheryl linoleate, propyl oleate, andisopropyl palmitate.

In one embodiment, the penetration enhancer is a glycol, such asdipropylene glycol, propylene glycol, butylene glycol or polyethyleneglycol. In other embodiments, the penetration enhancer comprisesglyceryl monooleate. In other embodiments, the penetration enhancercomprises a mixture of at least two penetration enhancers. For example,a penetration enhancer may comprise dipropylene glycol and glycerylmonooleate. As noted above, the inventors surprisingly discovered thateach of dipropylene glycol and glyceryl monooleate alone or incombination are effective enhancers for levonorgestrel.

In some embodiments, a penetration enhancer is used in an amount up toabout 30% by dry weight of the polymer matrix, including up to 30% byweight, up to about 20% by weight, including 20% by weight, or up toabout 10% by weight, up to 10% by weight, or up to 5% by weight,including up to 5% by weight, based on the dry weight of the polymermatrix. In some embodiments, a penetration enhancer is used in an amountof from about 5% to about 20%, including about 10% by weight.

The polymer matrix may further comprise various thickeners, fillers, andother additives or components known for use in transdermal drug deliverysystems.

As noted above, in embodiments where the polymer matrix comprises apressure-sensitive adhesive or bioadhesive, the polymer matrix can serveas an adhesive portion of the system (e.g., a reservoir device), or canserve as one or more layers of a multi-layer system. Alternatively, apolymer matrix comprising a pressure-sensitive adhesive or bioadhesivewith drug dissolved or dispersed therein can constitute a monolithicdevice. In embodiments where the polymer matrix does not comprise anadhesive, but instead, for example, comprises a polymeric drugreservoir, it can be used in combination with one or more adhesivelayers, or with a surrounding adhesive portion, as is well known tothose skilled in the art.

In some embodiments, the system consists essentially of the polymermatrix layer. By “consists essentially of the polymer matrix layer”means that the system does not contain any other layers that affect drugdelivery, such as an additional rate-controlling polymer layer,rate-controlling membrane, or drug reservoir layer. It will beunderstood, however, that the system that consists essentially of thepolymer matrix layer may comprise a backing layer and/or release liner.

The system may be of any shape or size suitable for transdermalapplication. The polymer matrices described herein may be prepared bymethods known in the art. The polymer matrices can be formed intosystems by methods known in the art. For example, the polymer matrixmaterial can be applied to a backing layer and release liner by methodsknown in the art, and formed into sizes and shapes suitable for use. Forexample, after the polymer matrix is formed, it may be brought intocontact with a support layer, such a releaser liner layer or backinglayer, in any manner known to those of skill in the art. Such techniquesinclude calender coating, hot melt coating, solution coating, etc.

For example, a polymer matrix can be prepared by blending the componentsof the polymer matrix, applying the matrix material to a support layersuch as a backing layer or release liner, and removing any remainingsolvents. The levonorgestrel and ethinyl estradiol can be added at anystage. In one embodiment, all polymer matrix components, includinglevonorgestrel and ethinyl estradiol, are blended together. In anotherembodiment, the polymer matrix components other than levonorgestrel andethinyl estradiol are blended together, and then the levonorgestrel andethinyl estradiol is dissolved or dispersed therein. The order of steps,amount of ingredients, and the amount and time of agitation or mixingcan be determined and optimized by the skilled practitioner. Anexemplary general method is as follows:

Appropriate amounts of polymer(s), levonorgestrel, ethinyl estradiol,enhancer(s), and organic solvent(s) (for example toluene, or ethylacetate an/or isopropyl alcohol) are combined and thoroughly mixedtogether in a vessel.

The formulation is then transferred to a coating operation where it iscoated onto a protective release liner at a controlled specifiedthickness. The coated product is then passed through an oven in order todrive off all volatile processing solvents.

The dried product on the release liner is then joined to the backingmaterial and wound into rolls for storage.

Appropriate size and shape “systems” are die-cut from the roll materialand then pouched.

Other manufacturing methods are known in the art that are suitable formaking the systems described herein.

In some embodiments, there is provided a method of effecting transdermaldrug delivery of levonorgestrel and ethinyl estradiol, by applying asystem as described herein to the skin or mucosa of a subject in needthereof. In some embodiments, the system is applied over a period of atleast about 1 day, at least about 2 days, at least about 3 days, atleast about 4 days, at least about 5 days, at least about 6 days, or atleast about 7 days, such as for 1, 2, 3, 4, 5, 6 or 7 days. In someembodiments, the method is effective to achieve therapeutic levels oflevonorgestrel and ethinyl estradiol in the subject during theapplication period.

In some embodiments, the systems described herein are designed for useby female patients, such as for contraception.

The following specific examples are included as illustrative of thetransdermal drug delivery systems and polymer matrices described herein.These examples are in no way intended to limit the scope of theinvention. Other aspects of the invention will be apparent to thoseskilled in the art to which the invention pertains.

EXAMPLE 1

A polymer matrix with the following composition is prepared:

% w/w in Finished Ingredient Dry Product Acrylic polymer 88.1 (Duro-Tak87-2516) Levonorgestrel 1.4 Ethinyl Estradiol 0.5 Glyceryl monooleate 10Total 100.00

The polymer matrix is applied to release liner and dried, a backingmaterial is applied, and transdermal drug delivery systems of a suitablesize are prepared

EXAMPLE 2

The polymer matrix of Example 1 was used to prepare transdermal drugdelivery systems. An in vitro flux study was conducted with humancadaver skin using a Franz cell apparatus to determine the flux of eachdrug from the matrix over a 160-hour (˜7 day) period, as compared to acorresponding commercial product. Results are shown FIGS. 1-2. FIG. 1illustrates the levonorgestrel flux (μg/cm²/hr) over time (0-160 hours)from a transdermal delivery system according to the invention (−), ascompared to Climara® Pro (▪). FIG. 2 illustrates the ethinyl estradiolflux (μg/cm²/hr) over time (0-160 hours) from a transdermal deliverysystem according to the invention (♦), as compared to OrthoEvra® (▪).

These data show that the systems described herein are able to achievesustained delivery of levonorgestrel and ethinyl estradiol over anextended period of time of about 7 days.

EXAMPLE 3

Polymer matrices with different relative amounts of ethinyl estradiolwere prepared as follows.

Sample 1 (♦) Sample 2 (▴) Sample 3 (-x-) % w/w in % w/w in % w/w inFinished Finished Finished Ingredient Dry Product Dry Product DryProduct Ethinyl Estradiol 0.5 1 1.5 Levonorgestrel 2 2 2 Kollidone VA 6420 20 20 (PVP/VA) Acrylic polymer 67.5 67.5 67.5 (Duro-Tak 87-2516)Glyceryl monooleate 10 10 10 Total 100.00

An in vitro flux study was conducted with human cadaver skin using aFranz cell apparatus to determine the flux of ethinyl estradiol from thematrices over a 160-hour (˜7 day) period. Results are shown in FIG. 3(♦,▴, -x-), as compared to OrthoEvra® (▪). These data show that the fluxof ethinyl estradiol can be selected and controlled by selecting andcontrolling the amount of ethinyl estradiol in the polymer matrix.

What is claimed is:
 1. A transdermal drug delivery system for thetransdermal delivery of levonorgestrel and ethinyl estradiol in the formof a flexible finite system for topical application, comprising apolymer matrix consisting of 0.1-3% by weight levonorgestrel, 0.1-5% byweight ethinyl estradiol, 5-20% by weight penetration enhancer, and thebalance hydroxy functional acrylic polymer.
 2. The transdermal drugdelivery system of claim 1, wherein the polymer matrix is substantiallyfree of polyvinylpyrrolidone (PVP) and polyvinylpyrrolidone/vinylacetate(PVP/VA).
 3. The transdermal drug delivery system of claim 1, whereinthe polymer matrix is free of polyvinylpyrrolidone (PVP) andpolyvinylpyrrolidone/vinylacetate (PVP/VA).
 4. The transdermal drugdelivery system of claim 1, wherein the penetration enhancer is selectedfrom the group consisting of glyceryl monooleate, dipropylene glycol,and mixtures thereof.
 5. The transdermal drug delivery system of claim1, comprising an amount of levonorgestrel sufficient to achievesustained delivery of levonorgestrel over a period of time of at least 3days, at least 4 days, or at least 7 days.
 6. The transdermal drugdelivery system of claim 1, comprising an amount of ethinyl estradiolsufficient to achieve sustained delivery of ethinyl estradiol over aperiod of time of at least 3 days, at least 4 days, or at least 7 days.7. The transdermal drug delivery system of claim 1, further comprising abacking layer.
 8. The transdermal drug delivery system of claim 1,further comprising a release liner.
 9. A method of transdermallydelivering levonorgestrel and ethinyl estradiol comprising applying atransdermal drug delivery system according to claim 1 to the skin ormucosa of a subject in need thereof.
 10. The method of claim 9, whereinthe subject is a human female subject.
 11. The method of claim 10,wherein the method is for contraception.
 12. The method of claim 9,wherein the transdermal drug delivery system is applied for a durationof up to 7 days.
 13. A method of preparing a transdermal drug deliverysystem comprising levonorgestrel and ethinyl estradiol in the form of aflexible finite system for topical application, comprising preparing apolymer matrix consisting of 0.1-3% by weight levonorgestrel, 0.1-5% byweight ethinyl estradiol, 5-20% by weight penetration enhancer, and thebalance hydroxyl functional acrylic polymer.
 14. The method of claim 13,wherein the polymer matrix is substantially free of polyvinylpyrrolidone(PVP) and polyvinylpyrrolidone/vinylacetate (PVP/VA).